Amphista Therapeutics' successful degradation of a key cancer target, BRD9, via a novel mechanism with DCAF16 E3 ligase published in Nature Communications

• The publication reports the highly selective, DCAF16 E3 enabled degradation of BRD9 in vivo using Amphista's proprietary, next generation Targeted Glue medicinal chemistry technology
• Amphista's scientists prospectively and rationally designed therapeutic molecules with a novel mechanism, intrinsic oral bioavailability and favourable drug-like properties
• Amphista's proprietary Targeted Glues offer an exciting new strategy for targeted protein degradation in acute myeloid leukaemia and other oncology and non-oncology indications
  
  

Cambridge, UK, 27 October 2025 - Amphista Therapeutics ("the Company" or "Amphista"), a leader in next generation targeted protein degradation (TPD), announced today that it has published data in the journal Nature Communications demonstrating, for the first time, a new mechanism of action for BRD9 degradation using the Company's novel Targeted Glue small molecule degrader.

Amphista's proprietary Targeted Glues are prospectively and rationally designed medicines. "The deep expertise of our scientists led to the successful integration of the favorable performance characteristics of earlier generation PROTACs and conventional molecular glues but with key limitations designed-out." commented Louise Modis, PhD, Chief Scientific Officer at Amphista Therapeutics.

As a result, Amphista's proprietary Targeted Glues specifically target a protein of interest with a ligand, like PROTACs, and like glues they stabilize interactions with a ligase. However, the resulting chemical modifications to the ligands generated with Amphista's medicinal chemistry attract specific non-cereblon (CRBN) and non-VHL-based ligases that recognize the neo protein interface and tag it for degradation.

The Nature Communications paper describes the design of a newly defined AMPTX-1 Targeted Glue and its ability to selectively and potently target BRD9 for degradation by inducing the formation of a ternary complex with DCAF16, a relatively uncharacterised E3 ligase that has not previously been successfully utilised for TPD in vivo. The key interaction between the Targeted Glue for BRD9 and DCAF16 has been mapped to a reversible covalent interaction with cysteine 58.

"What's really neat," Louise explains, "is that our Targeted Glues don't have any inherent affinity for the ligases on their own. This only occurs once the Targeted Glue has bound first to the protein of interest. For this reason, we describe our molecules as being 'sequentially bifunctional' to differentiate them from how traditional bifunctional molecules work, establishing a new approach for targeted protein degradation."

The Targeted Glue facilitated chemical modification to the targeted ligand is also smaller and more drug-like than conventional PROTAC binders and therefore offers the advantages of smaller molecules for drug development, similar to molecular glues.

"It is the first time that BRD9, a key protein involved in cancer, has been shown to be degraded using a non-CRBN or VHL mechanism," commentedGiles Brown, PhD Senior Vice President of Chemistry at Amphista Therapeutics. "Using our unique approach and deep scientific knowledge, we're showing how Amphista leads the way in creating a much-needed new generation of degraders."

Amphista's Targeted Glue therapeutics expand the range of E3 ligases that can be recruited therapeutically to specific targets to overcome the limitations of earlier generation CRBN and VHL-based PROTACs.

Louise Modis continued, "This novel discovery published in Nature Communications validates a new approach to targeted protein degradation and we look forward to carrying this positive momentum through our maturing pipeline of assets."

"We are rapidly unlocking the full potential of Targeted Glues by expanding our TPD toolbox of utilized E3 ligases to build new medicines that transform the lives of patients with severe diseases," added Giles Brown.

The full paper can be accessed here.

The publication follows announcements by Amphista unveiling novel differentiated mechanisms of action for the degradation of BRD9and TEAD, and first details of its SMARCA2HYPERLINK "https://amphista.com/amphista-therapeutics-discloses-first-details-of-its-smarca2-degrader-program/"SMARCA2 program.SMARCA2 program.

About Amphista Therapeutics

At Amphista Therapeutics, we are focused on transforming the lives of patients with severe diseases, including cancer and neurodegenerative disorders, through the discovery of advanced, next generation targeted protein degradation

Amphista, Eclipsys, Targeted Glue, Targeted Glues and the Amphista logo are all trademarks or registered trademarks of Amphista Therapeutics Limited.

For more information please contact:
Amphista Therapeutics
John Goodall
[e-mail]
ICR Healthcare
Amber Fennell, Namrata Taak, Emily Johnson
Email: [e-mail]

Tel: [phone]